Angiogenic growth factor mRNA responses to passive and contraction-induced hyperperfusion in skeletal muscle

1998 ◽  
Vol 85 (3) ◽  
pp. 1142-1149 ◽  
Author(s):  
Josep Roca ◽  
Timothy P. Gavin ◽  
Maria Jordan ◽  
Nikos Siafakas ◽  
Harrieth Wagner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Electrical Stimulation ◽  
Growth Factor ◽  
Acute Exercise ◽  
Transforming Growth Factor ◽  
Muscle Blood Flow ◽  
Mrna Levels ◽  
Angiogenic Growth Factor ◽  
Concentration Changes

It has been proposed that, in skeletal muscle, the angiogenic response to exercise may be signaled by the increase in muscle blood flow, via biomechanical changes in the microcirculation (increased shear stress and/or wall tension). To examine this hypothesis, we compared the change in abundance of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor-β1(TGF-β1) mRNA in skeletal muscles of the canine leg after 1 h of pump-controlled high blood flow alone (passive hyperperfusion; protocol A) and electrical stimulation of the femoral and sciatic nerves producing muscle contraction ( protocol B). The increase in leg blood flow (5.4- and 5.9-fold change from resting values, respectively) was similar in both groups. Passive hyperperfusion alone did not increase message abundance for VEGF (ratio of mRNA to 18S signals after vs. before hyperperfusion, 0.94 ± 0.08) or bFGF (1.08 ± 0.05) but slightly increased that of TGF-β1 (1.14 ± 0.07; P < 0.03). In contrast, as previously found in the rat, electrical stimulation provoked more than a threefold increase in VEGF mRNA abundance (3.40 ± 1.45; P < 0.02). However, electrical stimulation produced no significant changes in either bFGF (1.16 ± 0.13) or TGF-β1 (1.31 ± 0.27). These results suggest that the increased muscle blood flow of exercise does not account for the increased abundance of these angiogenic growth factor mRNA levels in response to acute exercise. We speculate that other factors, such as local hypoxia, metabolite concentration changes, or mechanical effects of contraction per se, may be responsible for the effects of exercise.

Effect of captopril on skeletal muscle angiogenic growth factor responses to exercise

2000 ◽  
Vol 88 (5) ◽  
pp. 1690-1697 ◽  
Author(s):  
Timothy P. Gavin ◽  
David A. Spector ◽  
Harrieth Wagner ◽  
Ellen C. Breen ◽  
Peter D. Wagner
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Acute Exercise ◽  
Transforming Growth Factor ◽  
Enzyme Inhibitor ◽  
Transforming Growth Factor Β ◽  
Mrna Levels ◽  
Vegf Mrna ◽  
Female Wistar Rats

Acute exercise increases vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and basic fibroblast growth factor (bFGF) mRNA levels in skeletal muscle, with the greatest increase in VEGF mRNA. VEGF functions via binding to the VEGF receptors Flk-1 and Flt-1. Captopril, an angiotensin-converting enzyme inhibitor, has been suggested to reduce the microvasculature in resting and exercising skeletal muscle. However, the molecular mechanisms responsible for this reduction have not been investigated. We hypothesized that this might occur via reduced VEGF, TGF-β1, bFGF, Flk-1, and Flt-1 gene expression at rest and after exercise. To investigate this, 10-wk-old female Wistar rats were placed into four groups ( n = 6 each): 1) saline + rest; 2) saline + exercise; 3) 100 mg/kg ip captopril + rest; and 4) 100 mg/kg ip captopril + exercise. Exercise consisted of 1 h of running at 20 m/min on a 10° incline. VEGF, TGF-β1, bFGF, Flk-1, and Flt-1 mRNA were analyzed from the left gastrocnemius by quantitative Northern blot. Exercise increased VEGF mRNA 4.8-fold, TGF-β1 mRNA 1.6-fold, and Flt-1 mRNA 1.7-fold but did not alter bFGF or Flk-1 mRNA measured 1 h after exercise. Captopril did not affect the rest or exercise levels of VEGF, TGF-β1, bFGF, and Flt-1 mRNA. Captopril did reduce Flk-1 mRNA 30–40%, independently of exercise. This is partially consistent with the suggestion that captopril may inhibit capillary growth.

Human VEGF gene expression in skeletal muscle: effect of acute normoxic and hypoxic exercise

1999 ◽  
Vol 277 (6) ◽  
pp. H2247-H2252 ◽  
Author(s):  
R. S. Richardson ◽  
H. Wagner ◽  
S. R. D. Mudaliar ◽  
R. Henry ◽  
E. A. Noyszewski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Acute Exercise ◽  
Work Rate ◽  
Northern Analysis ◽  
Endothelial Cell Proliferation ◽  
Vastus Lateralis Muscle ◽  
Mrna Levels ◽  
Vegf Mrna ◽  
Exercise Induced

Vascular endothelial growth factor (VEGF) is involved in extracellular matrix changes and endothelial cell proliferation, both of which are precursors to new capillary growth. Angiogenesis is a vital adaptation to exercise training, and the exercise-induced reduction in intracellular[Formula: see text] has been proposed as a stimulus for this process. Thus we studied muscle cell[Formula: see text] [myoglobin[Formula: see text]([Formula: see text])] during exercise in normoxia and in hypoxia (12% O2) and studied the mRNA levels of VEGF in six untrained subjects after a single bout of exercise by quantitative Northern analysis. Single-leg knee extension provided the acute exercise stimulus: a maximal test followed by 30 min at 50% of the peak work rate achieved in this graded test. Because peak work rate was not affected by hypoxia, the absolute and relative work rates were identical in hypoxia and normoxia. Three pericutaneous needle biopsies were collected from the vastus lateralis muscle, one at rest and then the others at 1 h after exercise in normoxia or hypoxia. At rest (control), VEGF mRNA levels were very low (0.38 ± 0.04 VEGF/18S). After exercise in normoxia or hypoxia, VEGF mRNA levels were much greater (16.9 ± 6.7 or 7.1 ± 1.8 VEGF/18S, respectively). In contrast, there was no measurable basic fibroblast growth factor mRNA response to exercise at this 1-h postexercise time point. Magnetic resonance spectroscopy of myoglobin confirmed a reduction in[Formula: see text] in hypoxia (3.8 ± 0.3 mmHg) compared with normoxia (7.2 ± 0.6 mmHg) but failed to reveal a relationship between [Formula: see text] during exercise and VEGF expression. This VEGF mRNA increase in response to acute exercise supports the concept that VEGF is involved in exercise-induced skeletal muscle angiogenesis but questions the importance of a reduced cellular [Formula: see text]as a stimulus for this response.

Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise

2000 ◽  
Vol 88 (4) ◽  
pp. 1192-1198 ◽  
Author(s):  
Timothy P. Gavin ◽  
David A. Spector ◽  
Harrieth Wagner ◽  
Ellen C. Breen ◽  
Peter D. Wagner
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Methyl Ester ◽  
Acute Exercise ◽  
Transforming Growth Factor ◽  
No Production ◽  
Vegf Mrna ◽  
Exercise Induced ◽  
Response To Exercise

Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor-β1 (TGF-β1) mRNA increase in rat skeletal muscle in response to a single acute exercise bout. Nitric oxide (NO) is released locally by muscle vascular endothelium and muscle fibers during exercise, contributes to the blood flow response to exercise, and regulates mitochondrial respiration. We hypothesized that a reduction in NO production, via NO synthase inhibition, would demonstrate a link between NO and the VEGF, bFGF, and TGF-β1 gene responses to exercise. To investigate this hypothesis, 9-wk-old female Wistar rats were divided into eight treatment groups ( n = 6 each): 1) saline + rest, 2) saline + exercise, 3) 30 mg/kg N ω-nitro-l-arginine methyl ester (l-NAME, a known NOS inhibitor) + rest, 4) 30 mg/kgl-NAME + exercise, 5) 300 mg/kg l-NAME + rest, 6) 300 mg/kg l-NAME + exercise, 7) 300 mg/kg N ω-nitro-d-arginine methyl ester (d-NAME, inactive enantiomer of l-NAME) + rest, and 8) 300 mg/kg d-NAME + exercise. Exercise consisted of 1 h of running at 20 m/min on a 10° incline. VEGF, TGF-β1, and bFGF mRNA from left gastrocnemius were analyzed by quantitative Northern blot. Submaximal exercise for 1 h increased VEGF mRNA 4.2-fold and TGF-β1 mRNA 1.5-fold in untreated rats but did not increase bFGF mRNA. The exercise-induced increase in VEGF mRNA was attenuated ∼50% by 30 and 300 mg/kgl-NAME; the TGF-β1 mRNA increase was unaffected by 300 mg/kg l-NAME. In addition, 300 mg/kgd-NAME had no effect on the exercise-induced increase in VEGF mRNA. Administration of 300 mg/kg l-NAME had no effect on bFGF mRNA. These findings suggest that NO is important in the regulation of the VEGF gene response to exercise through increases in VEGF transcription or by increases in the VEGF mRNA half-life.

Effect of NO, vasodilator prostaglandins, and adenosine on skeletal muscle angiogenic growth factor gene expression

1999 ◽  
Vol 86 (5) ◽  
pp. 1513-1518 ◽  
Author(s):  
H. Benoit ◽  
M. Jordan ◽  
H. Wagner ◽  
P. D. Wagner
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Regulation Of Gene Expression ◽  
Transforming Growth Factor Β1 ◽  
Angiogenic Growth Factor ◽  
Factor Gene ◽  
Growth Factor Gene

Exercise training results in several muscle adaptations, one of which is angiogenesis. Acutely, exercise leads to release of nitric oxide, prostacyclin (PGI2), and adenosine (A) in the skeletal muscles. In this paper, we asked whether any of these locally released vasodilators, as well as other known dilator prostaglandins (PGE1 and PGE2), have the potential to increase angiogenic growth factor gene expression in resting skeletal muscle. Seven groups of 5–7 female Wistar rats (age 8–12 wk, weight 250 ± 10 g) were anesthetized and instrumented for carotid artery pressure and electromagnetic femoral artery blood flow measurement. One group acted as control while the other groups each received one of the following six agents by constant arterial infusion (dose in μg/min): A (200), nitroprusside (NP, 4.2), acetylcholine (100), PGE1 (1.9), PGE2 (1.7), and PGI2 (1.7). Each agent reduced peripheral vascular resistance to a similar extent (at least twofold). Densitometric mRNA/18S levels for vascular endothelial growth factor (VEGF) were increased 50% by NP and acetylcholine, were unaffected by PGE1 and PGE2, and were reduced 40% by PGI2. For basic fibroblast growth factor, only PGI2 had any effect, reducing mRNA/18S ∼25%. For transforming growth factor-β1, A, NP, and PGE1 led to reduced mRNA/18S, whereas PGE2 slightly increased mRNA/18S. For the principal putative angiogenic growth factor, VEGF, these data suggest that naturally secreted vasodilators in contracting skeletal muscle could be involved in regulation of gene expression, namely, nitric oxide in a positive and PGI2 in a negative direction.

Acute ethanol increases angiogenic growth factor gene expression in rat skeletal muscle

2002 ◽  
Vol 92 (3) ◽  
pp. 1176-1182 ◽  
Author(s):  
Timothy P. Gavin ◽  
Peter D. Wagner
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Acute Exercise ◽  
Muscle Growth ◽  
Angiogenic Growth Factor ◽  
Factor Gene ◽  
Skeletal Muscle Growth ◽  
Growth Factor Gene ◽  
Exercise Induced

Moderate ethanol consumption demonstrates a protective effect against cardiovascular disease and improves insulin sensitivity, possibly through angiogenesis. We investigated whether 1) ethanol would increase skeletal muscle growth factor gene expression and 2) the effects of ethanol on skeletal muscle growth factor gene expression were independent of exercise-induced growth factor gene expression. Female Wistar rats were used. Four groups (saline + rest; saline + exercise; 17 mmol/kg ethanol + rest; and 17 mmol/kg ethanol + exercise) were used to measure the growth factor response to acute exercise and ethanol administration. Vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), basic fibroblast growth factor (bFGF), Flt-1, and Flk-1 mRNA were analyzed from the left gastrocnemius by quantitative Northern blot. Ethanol increased VEGF, TGF-β1, bFGF, and Flt-1 mRNA at rest and after acute exercise. Ethanol increased resting Flk-1 mRNA. Ethanol increased bFGF mRNA independently of exercise. These findings suggest that 1) ethanol can increase skeletal muscle angiogenic growth factor gene expression and 2) the mechanisms responsible for the ethanol-induced increases in VEGF, TGFβ1, and Flt-1 mRNA appear to be different from those responsible for exercise-induced regulation. Therefore, these results provide evidence in adult rat tissue that the protective cardiovascular effects of moderate ethanol consumption may result in part through the increase of angiogenic growth factors.

VEGF receptor antagonism blocks arteriogenesis, but only partially inhibits angiogenesis, in skeletal muscle of exercise-trained rats

2005 ◽  
Vol 288 (2) ◽  
pp. H759-H768 ◽  
Author(s):  
Pamela G. Lloyd ◽  
Barry M. Prior ◽  
Han Li ◽  
Hsiao T. Yang ◽  
Ronald L. Terjung
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Growth Factor ◽  
Exercise Training ◽  
Tyrosine Kinase ◽  
Muscle Blood Flow ◽  
Vegf Receptor ◽  
Collateral Vessel ◽  
Collateral Artery ◽  
Ischemic Muscle

Both collateral vessel enlargement (arteriogenesis) and capillary growth (angiogenesis) in skeletal muscle occur in response to exercise training. Vascular endothelial growth factor (VEGF) is implicated in both processes. Thus we examined the effect of a VEGF receptor (VEGF-R) inhibitor (ZD4190, AstraZeneca) on collateral-dependent blood flow in vivo and collateral artery size ex vivo (indicators of arteriogenesis) and capillary contacts per fiber (CCF; an index of angiogenesis) in skeletal muscle of both sedentary and exercise-trained rats 14 days after bilateral occlusion of the femoral arteries. Total daily treadmill run time increased appreciably from ∼70 to ∼100 min (at 15–20 m/min, twice per day) and produced a large (∼75%, P < 0.01) increase in calf muscle blood flow and a greater size of the collateral artery (wall cross-sectional area). ZD4190, which previously has been shown to inhibit the activity of VEGF-R2 and -R1 tyrosine kinase in vitro (IC50 = 30 and 700 nM, respectively), completely blocked the increase in collateral-dependent blood flow and inhibited collateral vessel enlargement. Thus exercise-stimulated collateral arteriogenesis appears to be completely dependent on VEGF-R signaling. Interestingly, enhanced mRNA expression of the VEGF family ligand placental growth factor (2- to 3.5-fold), VEGF-R1 (∼2-fold), and endothelial nitric oxide synthase (2- to 3.5-fold) in an isolated collateral artery implicates these factors as important in arteriogenesis. Training of ischemic muscle also induced angiogenesis, as shown by an increase (∼25%, P < 0.01) in CCF in white gastrocnemius muscle. VEGF-R inhibition only partially blocked ( P < 0.01) but did not eliminate the increase ( P < 0.01) in capillarity. Our findings indicate that VEGF-R tyrosine kinase activity is essential for collateral arteriogenesis and important for the angiogenesis induced in ischemic muscle by exercise training; however, other angiogenic stimuli are also important for angiogenesis in flow-limited active muscle.

scholarly journals The influence of physical training on the angiopoietin and VEGF-A systems in human skeletal muscle

2007 ◽  
Vol 103 (3) ◽  
pp. 1012-1020 ◽  
Author(s):  
T. Gustafsson ◽  
H. Rundqvist ◽  
J. Norrbom ◽  
E. Rullman ◽  
E. Jansson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Vastus Lateralis ◽  
Exercise Bout ◽  
Voluntary Exercise ◽  
Vastus Lateralis Muscle ◽  
Mrna Levels ◽  
Ki 67

Eleven subjects performed one-legged exercise four times per week for 5 wk. The subjects exercised one leg for 45 min with restricted blood flow (R leg), followed by exercise with the other leg at the same absolute workload with unrestricted blood flow (UR leg). mRNA and protein expression were measured in biopsies from the vastus lateralis muscle obtained at rest before the training period, after 10 days, and after 5 wk of training, as well as 120 min after the first and last exercise bouts. Basal Ang-2 and Tie-1 mRNA levels increased in both legs with training. The Ang-2-to-Ang-1 ratio increased to a greater extent in the R leg. The changes in Ang-2 mRNA were followed by similar changes at the protein level. In the R leg, VEGF-A mRNA expression responded transiently after acute exercise both before and after the 5-wk training program. Over the course of the exercise program, there was a concurrent increase in basal VEGF-A protein and VEGFR-2 mRNA in the R leg. Ki-67 mRNA showed a greater increase in the R leg and the protein was localized to the endothelial cells. In summary, the increased translation of VEGF-A is suggested to be caused by the short mRNA burst induced by each exercise bout. The concurrent increase in the Ang-2-to-Ang-1 ratio and the VEGF-expression combined with the higher level of Ki-67 mRNA in the R leg indicate that changes in these systems are of importance also in nonpathological angiogenic condition such as voluntary exercise in humans. It further establish that hypoxia/ischemia-related metabolic perturbation is likely to be involved as stimuli in this process in human skeletal muscle.

Neural control of glucose uptake by skeletal muscle after central administration of NMDA

1995 ◽  
Vol 268 (2) ◽  
pp. R492-R497 ◽  
Author(s):  
C. H. Lang ◽  
M. Ajmal ◽  
A. G. Baillie
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Glucose Uptake ◽  
Neural Control ◽  
Plasma Insulin ◽  
Regional Blood Flow ◽  
Muscle Blood Flow ◽  
Whole Body ◽  
Glucose Disposal ◽  
Central Administration

Intracerebroventricular injection of N-methyl-D-aspartate (NMDA) produces hyperglycemia and increases whole body glucose uptake. The purpose of the present study was to determine in rats which tissues are responsible for the elevated rate of glucose disposal. NMDA was injected intracerebroventricularly, and the glucose metabolic rate (Rg) was determined for individual tissues 20-60 min later using 2-deoxy-D-[U-14C]glucose. NMDA decreased Rg in skin, ileum, lung, and liver (30-35%) compared with time-matched control animals. In contrast, Rg in skeletal muscle and heart was increased 150-160%. This increased Rg was not due to an elevation in plasma insulin concentrations. In subsequent studies, the sciatic nerve in one leg was cut 4 h before injection of NMDA. NMDA increased Rg in the gastrocnemius (149%) and soleus (220%) in the innervated leg. However, Rg was not increased after NMDA in contralateral muscles from the denervated limb. Data from a third series of experiments indicated that the NMDA-induced increase in Rg by innervated muscle and its abolition in the denervated muscle were not due to changes in muscle blood flow. The results of the present study indicate that 1) central administration of NMDA increases whole body glucose uptake by preferentially stimulating glucose uptake by skeletal muscle, and 2) the enhanced glucose uptake by muscle is neurally mediated and independent of changes in either the plasma insulin concentration or regional blood flow.

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